细胞凋亡和肿瘤07(简).ppt

细胞凋亡与肿瘤 广西医科大学病理教研室 罗殿中 细胞死亡的认识过程 Virchow (1858): 将细胞死亡定义为：细胞退化（degeneration), 软化（softening), 坏死（necrosis). Flemming (1885): 观察到染色质凝聚和细胞核渐进性退化、消失，称之为染色质裂解（chromatolysis). Glucksman (1951): 发现细胞在生物发育过程中死亡，提出程序化细胞死亡（programmed cell death). 细胞死亡的认识过程 Kerr (1971): 结扎门静脉诱导肝细胞缺血，发现肝细胞死亡的独特形式（细胞变小，染色质碎裂），称之为固缩性坏死（shrinkage necrosis). Kerr 等(1972): 提出细胞凋亡（apoptosis)。 1976-1981: 发现细胞凋亡伴随典型的“梯样” DNA 电泳图谱。 Wyllie(1984): 提出细胞凋亡伴随内源性核酸酶的激活。 Features of Apoptosis Vs Necrosis1972 Kerr, Wyllie, Currie 细胞死亡新形式---entosis 有些细胞会进入到其它细胞中,然后死亡，称为entosis。(Cell, 2007) 细胞凋亡的生物学意义 1. Programmed cell death is as needed for proper development as mitosis is. Examples: 2. PCD is needed to destroy cells that represent a threat to the integrity of the organism. Examples: Cells infected with viruses virus-infected cells could be killed by CTLs. Cells with DNA damage Cancer cells 细胞凋亡的原因 The balance between: the withdrawal of positive signals; that is, signals needed for continued survival the receipt of negative signals 细胞凋亡的原因 Withdrawal of positive signals The continued survival of most cells requires that they receive continuous stimulation from other cells. Some examples of positive signals: growth factors for neurons IL-2 an essential factor for the mitosis of lymphocytes 细胞凋亡的原因 Receipt of negative signals the damaged DNA by oxidants, x-rays etc molecules that bind to specific receptors on the cell surface and signal the cell to begin the apoptosis program. These death activators include: --Tumor necrosis factor - a (TNF-α ) that binds to the TNF receptor. --Lymphotoxin (also known as TNF-β ) that binds to the TNF receptor; --Fas ligand (FasL), that binds to Fas (CD95) Genes implicated in ApoptosisToo many to count Fas, Trail, TNF (Receptor and Ligand) Bcl-2 family (~12) Kinases RIP3, CAP, AKT, PKA, MapK Mitochondrial Proteins VDAC ANT Cytochrome C AIF SMAC Proteases Caspases (~13) (originally ICE), Granzyme Calpain Caspase regulators IAP/ Survivin (~5), APAF1